My goal is to become a physician-scientist investigating basic mechanisms of neurodegenerative disease, specifically Parkinson's disease. I obtained an MD/PhD from Emory University under the direction of Allan Levey. I studied the interaction between the Notch signaling pathway and the Alzheimer's disease-linked presenilin genes, using cellular models and basic molecular biology techniques. During my PhD work, I obtained two grants to fund my work and published two manuscripts. I completed my residency in neurology at the Weill-Cornell Medical Center, where I was named Chief Resident my final year. Next, I came to Columbia for fellowship training in movement disorders. I have developed my clinical skills in caring for patients with movement disorders, primarily Parkinson's disease. During my second year of fellowship (July 2008) I returned to full-time bench research. Since joining the lab I have authored a review article on cell death mechanisms in Parkinson's disease. In sum, I have demonstrated a strong commitment to research throughout all phases of my training, and I believe that I have shown the ability to succeed in carrying out research. I decided to perform my fellowship training at Columbia because it was an ideal location for advancing my career. Columbia's Movement Disorders Division provides excellent clinical training and resources for clinical and translational research. More importantly, Columbia's research environment in neuroscience is outstanding. Specifically, the diverse range of research interests coupled with the high degree of collaboration was very appealing. In addition to its faculty, the University has first-rate facilities, ample institutional funding, and active academic events. When choosing a mentor, I wanted someone who could teach me a novel set of techniques and approaches, but shared my interest in using cellular models to address questions related to disease mechanisms. I chose Lloyd Greene for several reasons: he is a senior faculty member with a strong record of training scientists at my career stage; he is an expert in cell death mechanisms and has an active project in PD-related cell death; he collaborates closely with other researchers in multiple areas of PD research; the techniques and approaches used in the lab are important ones that I have no experience with, e.g. primary neuronal cultures, the use of lentivirus for high efficiency transduction, and RNA interference. My research proposal focuses on Parkinson's disease (PD), a common neurodegenerative disease that causes significant disability. The development of neuroprotective therapies is a pressing need in PD, but this requires a better understanding of the mechanisms of neuronal death in the disease. The Greene lab has studied transcriptionally regulated genes that contribute to either cell death or survival in PD. One of these, a protein called RTP801, appears to be essential for cell death in PD models and is upregulated in affected neurons in the disease. To date, RTP801 has been evaluated in toxin-based models of PD. In order to further validate the role of RTP801 in PD pathogenesis, we will test the role of RTP801 in alpha-synuclein-mediated cell death (Specific Aim 1). The regulation of RTP801 occurs primarily at the transcriptional level, but RTP801 regulation has not been studied in neuronal systems or and in response to stressors relevant to PD. Identifying the transcription factor(s) involved in RTP801 upregulation during stressors relevant to PD may provide potential targets for neuroprotective therapies. Therefore, we will identify the transcription factor(s) important for regulating RTP801 in response to PD-relevant stressors (Specific Aim 2). We have studied the transcription factor ATF4 as a potential regulator of RTP801 and cell death, since ATF4 activity is involved in increasing RTP801 expression in other systems. In preliminary experiments, we found that ATF4 is not required for RTP801 upregulation by 6OHDA. Furthermore, 6OHDA-induced cell death was exacerbated by decreasing ATF4 levels, suggesting that ATF4 may be protective. If so, augmenting ATF4 activity might be a strategy for delaying neuronal cell death in PD. We will further define the role of ATF4 in toxin-mediated cell death and RTP801 upregulation. Furthermore, we plan to test the notion that ATF4 activity is neuroprotective in PD in the 1Syn cellular model mentioned above and the in vivo MPTP model using ATF4-null mice (Specific Aim 3). In conclusion, this career development award is essential for enabling me to become an independent physician-scientist. Having been away from bench research for more than 7 years, I need to re-establish a project and line of research, essentially from scratch. For bench research, the ability to limit my clinical responsibilities and spend the majority of my time in lab is crucial for success. During the period of the award, I will spend 80% of my time performing research; the remainder of the time will be spent in clinical care of PD patients and teaching. Over the course of the grant, I will gain experience with a group of approaches and systems that will allow me to explore fundamental disease mechanisms in PD. I will develop a theme of research regarding the beneficial and harmful effects of stress-related proteins and pathways in PD. As the award draws to a close, I will use the story and findings I have developed as a foundation for obtaining independent research funding.